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in vivo and in vitro. In the same study, TNF-α induced aneurysms has demonstrated macrophage infiltration
increased expression of Kruppel-like transcription within aneurysmal walls. [59,60,110] Chalouhi et al. [73]
factor 4, a known regulator of VSMC differentiation. [102] found high plasma concentrations of MCP-1 within the
Additional studies have identified cigarette smoke, a lumens of intracranial aneurysms, suggesting active
known potent pro-inflammatory stimulus, to induce recruitment of macrophages and other inflammatory
similar phenotypic changes in VSMCs, including cells.
increased secretion of TNF-α. [100] Clearly the data shows
TNF-α secretion to be involved in a positive feedback There is mounting evidence that macrophage invasion
loop with VSMCs, with TNF-α stimulating phenotypic may be a causal factor in rupture. Frosen et al. [60] found
change and thus driving its own secretion from these more prominent macrophage infiltration in ruptured
cells. The fact that VSMCs appear to first exhibit aneurysms compared to that found in unruptured
pathologic migration, followed by disappearance prior aneurysms. Of particular interest was the infiltration

to rupture suggests TNF-α first induces phenotypic of macrophages observed within the first 12 h after
change that is followed by apoptosis in the presence of rupture, suggesting that macrophages may induce
chronically sustained levels of the cytokine. [103] the rupture. MRI investigations of aneurysms with
ferumoxytol (AMAG Pharmaceuticals, Lexington,
INFLAMMATORY CELL MIGRATION AND Massachusetts, USA), a superparamagnetic iron oxide
INFILTRATION particle cleared by macrophages, have also linked
macrophage infiltration with rupture. [111-113] In a study
Endothelial cell dysfunction and apoptosis increase of 48 unruptured aneurysms, all aneurysms that
the permeability of vessel walls, allowing for enhanced showed early uptake of ferumoxytol on MRI ruptured
binding and transmigration of inflammatory cells within 6 months. [114] Among aneurysms demonstrating
into the underlying VSMC layer. T-cells have been late uptake, there were no ruptures or increase in size
demonstrated within aneurysm walls where they during the follow-up period. Immunohistochemical
respond to antigen presentation by monocytes and analysis found greater levels of inflammation in
macrophages. [104] In a rat model, mast cells were aneurysms with early uptake of ferumoxytol. The
significantly increased within the walls of forming authors propose that early uptake of ferumoxytol
cerebral aneurysms. [105] Inhibition of mast cell is associated with more prominent inflammation,
degranulation diminished aneurysm size, prevented increased macrophage infiltration, and thus, a greater
thinning of the tunica media, blocked NF-κB activation, risk of rupture. Follow-up investigations utilizing
and decreased expression of MCP-1, MMP, and IL-1β. aspirin as an anti-inflammatory agent found a decrease
An evaluation of human intracerebral aneurysms found in aneurysm wall signal intensity on ferumoxytol
mast cells to be significantly increased in ruptured MRI and a diminished number of macrophages on
compared to unruptured aneurysms. [106] These findings immunostaining. [111] Hasan et al. [106] examined the
suggest mast cells play an important role in aneurysm M1 (pro-inflammatory) and M2 (anti-inflammatory)
growth and rupture. subsets of macrophages in a population of ruptured
and unruptured clipped aneurysms. While M1 and

Monocytes and macrophages appear to be essential to M2 macrophages were observed in equal proportions
aneurysm formation and rupture, a finding that has in unruptured aneurysms, M1 macrophages were
been repeatedly demonstrated in animal and clinical found in a significantly greater proportion in ruptured
studies. These cells secrete MMPs and elastases which aneurysms.
are responsible for degradation of the extracellular
matrix and the internal elastic lamina. [107] Kanematsu Therapeutic implications
et al. [108] observed macrophage depletion and inhibition Current treatment options for ruptured and unruptured
of MCP-1 to be associated with a reduced incidence of cerebral aneurysms include microsurgical and

intracranial aneurysms. Aoki et al. [72] also observed a endovascular obliteration. These interventions are
significant decrease in cerebral aneurysm formation, associated with a significant morbidity and mortality,
macrophage accumulation, and expression of MMP-2 the risk that is magnified in cases of asymptomatic

and MMP-9 in MCP-1 deficient mice.In a murine model, unruptured aneurysms. Thus, study of the mechanisms
Ruzevick et al. [109] observed the haptoglobin 2-2 (Hp2-2) underlying aneurysm evolution is critical to establish
genotype, which is linked to a pro-inflammatory state, a better understanding of which aneurysms are more
to be associated with significantly larger aneurysms likely to rupture. Additionally, this data may provide
and a greater number of macrophages within the insight into the biological pathways best-suited for

aneurysm walls. Histopathological examination pharmacological intervention, stabilization of the
of ruptured and unruptured human intracranial aneurysm wall, and prevention of rupture. The

72 Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015